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The purpose of this study was to investigate the impact of conjugated estrogen cream, in conjunction with progesterone, on the endometrium, following vaginal administration, and assess the combined dose–effect relationship with progesterone. Initially, bilateral ovaries from mature, female, Sprague Dawley rats were excised to establish a hypoestrogenic (perimenopausal) model. A conjugated estrogen–progesterone combination cream was administered vaginally for a duration of 12 days. Subsequently, this study used pathological sections, Enzyme-Linked Immunosorbent Assay (ELISA) for pharmacodynamic studies, network pharmacology to explore possible signalling pathways associated with the drug and menopausal syndrome, and partial validation using a real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (ICH). The results demonstrate that, relative to the model group, the conjugated estrogen monotherapy significantly increased the uterine weight coefficients (p < 0.0001) and endometrial thickness (p < 0.001) and upregulated the expression of Cyclin D1 and VEGF. Moreover, this treatment downregulated PTEN expression. The co-administration of progesterone reversed these effects in a dose-dependent manner. Overall, the vaginal administration of a combination of progesterone and conjugated estrogen cream demonstrated the ability to mitigate endometrial hyperplasia induced by conjugated estrogen vaginal cream monotherapy. Furthermore, the effect of progesterone exhibited a dose-dependent response.

IntroductionNut quality detection is of paramount importance in primary nut processing. When striving to maintain the imperatives of rapid, efficient, and accurate detection, the precision of identifying small-sized nuts can be substantially compromised.MethodsWe introduced an optimized iteration of the YOLOv5s model designed to swiftly and precisely identify both good and bad walnut nuts across multiple targets. The M3-Net network, which is a replacement for the original C3 network in MobileNetV3’s YOLOv5s, reduces the weight of the model. We explored the impact of incorporating the attention mechanism at various positions to enhance model performance. Furthermore, we introduced an attentional convolutional adaptive fusion module (Acmix) within the spatial pyramid pooling layer to improve feature extraction. In addition, we replaced the SiLU activation function in the original Conv module with MetaAconC from the CBM module to enhance feature detection in walnut images across different scales.ResultsIn comparative trials, the YOLOv5s_AMM model surpassed the standard detection networks, exhibiting an average detection accuracy (mAP) of 80.78%, an increase of 1.81%, while reducing the model size to 20.9 MB (a compression of 22.88%) and achieving a detection speed of 40.42 frames per second. In multi-target walnut detection across various scales, the enhanced model consistently outperformed its predecessor in terms of accuracy, model size, and detection speed. It notably improves the ability to detect multi-target walnut situations, both large and small, while maintaining the accuracy and efficiency.DiscussionThe results underscored the superiority of the YOLOv5s_AMM model, which achieved the highest average detection accuracy (mAP) of 80.78%, while boasting the smallest model size at 20.9 MB and the highest frame rate of 40.42 FPS. Our optimized network excels in the rapid, efficient, and accurate detection of mixed multi-target dry walnut quality, accommodating lightweight edge devices. This research provides valuable insights for the detection of multi-target good and bad walnuts during the walnut processing stage.

By targeting the membrane (M) proteins of monkeypox virus (MPXV) strain VEROE6, we analyzed its evolutionary hierarchy and predicted its dominant antigenic B-cell epitope to provide a theoretical basis for the development of MPXV epitope vaccines and related monoclonal antibodies. In this study, phylogenetic trees were constructed based on the nucleic acid sequences of MPXV and the amino acid sequences of M proteins. The 3D structure of the MPXV_VEROE6 M proteins was predicted with AlphaFold v2.0 and the dominant antigenic B-cell epitopes were comprehensively predicted by analyzing parameters such as flexible segments, the hydrophilic index, the antigenic index, and the protein surface probability. The results showed that the M protein of MPXV_VEROE6 contained 377 amino acids, and their spatial configuration was relatively regular with a turning and random coil structure. The results of a comprehensive multiparameter analysis indicated that possible B-cell epitopes were located in the 23–28, 57–63, 67–78, 80–93, 98–105, 125–131, 143–149, 201–206, 231–237, 261–270, 291–303, and 346–362 amino acid segments. This study elucidated the structural and evolutionary characteristics of MPXV membrane proteins with the aim of providing theoretical information for the development of epitope vaccines, rapid diagnostic reagents, and monoclonal antibodies for monkeypox virus.

It is essential to ensure stability during marine transportation or the installation of high center of gravity loads. The heavy loads increase gravity disturbance, affecting the steady-state-error control of the multiple degrees of freedom (DOFs) motion compensation platform. In this paper, we propose a proportional derivative (PD) controller with dynamic gravity compensation (PDGC) for a 3-RCU (revolute–cylindrical–universal) parallel platform to improve the control effect of marine motion compensation for high center of gravity loads. We introduce an evaluation parameter of load stability and a weighting coefficient of anti-swaying control to tune the controller performance. The controller can set its control target between the two, keeping the load contact surface level and allowing the load center of gravity with the least movement. By deriving the Jacobian matrix, the gravity disturbance in the joint space is calculated and is compensated in the controller. First, we verify the control superiority of this controller over the PD controller under sinusoidal excitation in simulation and validate the effectiveness of the proposed anti-swing strategy. Then, the experiments are conducted with random excitation. The root mean square (RMS) value of the load’s residual angle with the proposed controller is reduced to 32.2% and 17.6% in two directions, respectively, compared with the PD controller under class 4 sea state excitation. The proposed method is effective for the anti-swaying control of ship-mounted 3-RCU parallel platforms.

Pigs are important large animal models for biomedical research. Here, the authors construct a single-cell landscape of pig tissues, unravelling the phenotypic heterogeneity of blood endothelial cells in adipose tissues and the evolutionally conserved regulons of microglia in brains.

Abstract: Based on theoretical analysis, we select the relevant data of 30 provinces (autonomous regions and municipalities) in China from 2013 to 2019, and empirically test the impact of financial technology on the development of big data industry and its mechanism using dynamic panel data model, mediating effect test method and threshold effect model. The benchmark regression results show that the regression coefficient of financial technology to big data industry is significantly positive at the significance level of 10%, indicating that the financial technology can directly promote the development of big data industry. The regression coefficient of the dynamic lag term of big data industry is negative, but not significant, indicating that the dynamic lag effect of big data industry is not obvious. The mediating effect test results show that the financial technology can indirectly promote the development of big data industry by alleviating the big data enterprise financing constraints. The big data enterprise financing constraints have a partial mediating effect, and the mediating effect account for 27.63% of the total effect. In addition, the threshold effect test results show that the direct effect of financial technology on big data industry is significantly enhanced when the development level of financial technology is higher than 5.8790, that is, there is a positive threshold effect of financial technology directly promoting the development of big data industry. However, the indirect effect of financial technology on big data industry is relatively weak when the development level of financial technology is higher than 5.4328, that is, financial technology indirectly promotes the development of big data industry by alleviating the big data enterprise financing constraints, which has a negative threshold effect.

Abstract Background The exact animal origin of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains obscure and understanding its host range is vital for preventing interspecies transmission. Methods Herein, we applied single‐cell sequencing to multiple tissues of 20 species (30 data sets) and integrated them with public resources (45 data sets covering 26 species) to expand the virus receptor distribution investigation. While the binding affinity between virus and receptor is essential for viral infectivity, understanding the receptor distribution could predict the permissive organs and tissues when infection occurs. Results Based on the transcriptomic data, the expression profiles of receptor or associated entry factors for viruses capable of causing respiratory, blood, and brain diseases were described in detail. Conserved cellular connectomes and regulomes were also identified, revealing fundamental cell‐cell and gene‐gene cross‐talks from reptiles to humans. Conclusions Overall, our study provides a resource of the single‐cell atlas of the animal kingdom which could help to identify the potential host range and tissue tropism of viruses and reveal the host‐virus co‐evolution.

Abstract Background During pregnancy, mother–child interactions trigger a variety of subtle changes in the maternal body, which may be reflected in the status of peripheral blood mononuclear cells (PBMCs). Although these cells are easy to access and monitor, a PBMC atlas for pregnant women has not yet been constructed. Methods We applied single‐cell RNA sequencing (scRNA‐seq) to profile 198,356 PBMCs derived from 136 pregnant women (gestation weeks 6 to 40) and a control cohort. We also used scRNA‐seq data to establish a transcriptomic clock and thereby predicted the gestational age of normal pregnancy. Results We identified reconfiguration of the peripheral immune cell phenotype during pregnancy, including interferon‐stimulated gene upregulation, activation of RNA splicing‐related pathways and immune activity of cell subpopulations. We also developed a cell‐type‐specific model to predict gestational age of normal pregnancy. Conclusions We constructed a single‐cell atlas of PBMCs in pregnant women spanning the entire gestation period, which should help improve our understanding of PBMC composition turnover in pregnant women.

As one of the multidisciplinary design optimization methods, the collaborative optimization (CO) can enjoy a high degree of discipline autonomy. It has received extensive attention and been used in the modern engineering design process. However, the original CO is low optimization accuracy and efficiency for the design of high-dimensional nonlinearity systems because of the involved compatibility constraints. To solve this problem, an enhanced CO method based on the adaptive surrogate model is proposed in this study. The strategy of the proposed method includes the following steps. Firstly, the traditional surrogate models of system objective and performance function are constructed by the Latin hypercube sampling and the Kriging method. Then, the expected improvement function and the self-cycling optimization strategy are utilized to modify the traditional surrogate models into the corresponding adaptive surrogate models. Finally, the original objective and constraints at the system level and disciplinary level are replaced by their adaptive surrogate models, respectively. Consequently, the formulation of CO based on the adaptive surrogate model can be obtained. In the proposed method, the accuracy of the non-linear region of the response surface can be enhanced efficiently. An engineering structure design problem is introduced to show the effectiveness of the proposed method.

Ciboria carunculoides is the dominant causal agent of mulberry sclerotial disease, and it is a necrotrophic fungal pathogen with a narrow host range that causes devastating diseases in mulberry fruit. However, little is known about the interaction between C. carunculoides and mulberry. Here, our transcriptome sequencing results showed that the transcription of genes in the secondary metabolism and defense-related hormone pathways were significantly altered in infected mulberry fruit. Due to the antimicrobial properties of proanthocyanidins (PAs), the activation of PA biosynthetic pathways contributes to defense against pathogens. Salicylic acid (SA) and jasmonic acid (JA) are major plant defense hormones. However, SA signaling and JA signaling are antagonistic to each other. Our results showed that SA signaling was activated, while JA signaling was inhibited, in mulberry fruit infected with C. carunculoides. Yet SA mediated responses are double-edged sword against necrotrophic pathogens, as SA not only activates systemic acquired resistance (SAR) but also suppresses JA signaling. We also show here that the small secreted protein CcSSP1 of C. carunculoides activates SA signaling by targeting pathogenesis-related protein 1 (PR1). These findings reveal that the infection strategy of C. carunculoides functions by regulating SA signaling to inhibit host defense responses.

The turbine rotor is the key component of the turbine, which has a great impact on the construction cost and power generation efficiency of an entire hydropower station. Receiving the torque of the runner transmission and completing the specified power generation is its main function. There are many uncertain factors in the design, manufacture, and operation environment of a turbine rotor. Therefore, it is necessary to optimize the mechanism on the premise of ensuring that the mechanical system meets high reliability and high safety levels. This article uses the multidisciplinary reliability analysis and optimization method under random and interval uncertainty to quantitatively analyze the uncertainty factors, and then optimally solves the RBMDO problem of the turbine rotor mechanism. Through the finite element simulation analysis of the optimized design scheme, the rationality and feasibility of the obtained results are further verified.

Scleromitrula shiraiana is a necrotrophic fungus with a narrow host range, and is one of the main causal pathogens of mulberry sclerotial disease. However, its molecular mechanisms and pathogenesis are unclear. Here, we report a 39.0 Mb high-quality genome sequence for S. shiraiana strain SX-001. The S. shiraiana genome contains 11,327 protein-coding genes. The number of genes and genome size of S. shiraiana are similar to most other Ascomycetes. The cross-similarities and differences of S. shiraiana with the closely related Sclerotinia sclerotiorum and Botrytis cinerea indicated that S. shiraiana differentiated earlier from their common ancestor. A comparative genomic analysis showed that S. shiraiana has fewer genes encoding cell wall-degrading enzymes (CWDEs) and effector proteins than that of S. sclerotiorum and B. cinerea, as well as many other Ascomycetes. This is probably a key factor in the weaker aggressiveness of S. shiraiana to other plants. S. shiraiana has many species-specific genes encoding secondary metabolism core enzymes. The diversity of secondary metabolites may be related to the adaptation of these pathogens to specific ecological niches. However, melanin and oxalic acid are conserved metabolites among many Sclerotiniaceae fungi, and may be essential for survival and infection. Our results provide insights into the narrow host range of S. shiraiana and its adaptation to mulberries.

Currently, anti-obesity drugs are limited by their high costs and numerous adverse effects. In this study, collagen peptide (CP), with molecular weights ranging from 500 to 5000, was enzymatically hydrolyzed using Walleye pollock skin. We further demonstrated the effective anti-obesity effects of CP in a High-Fat Diet-Fed Mice. The microbial analysis showed that CP treatment could regulate the overall composition of the gut microbiota. Specifically, CP intervention increased the relative abundance of Lactobacillus, Akkermansia, Parabacteroides, and Odoribacter spp. CP intervention decreased the abundance of intestinal inflammation bacteria, such as Erysipelatoclostridium and Alistipes. To the best of our knowledge, this study was the first of its kind to provide evidence that CP could restore the composition of the gut microbiota destroyed in the HFD mouse model. These results indicate that CP from Walleye pollock skin is a potential agent for further development as an adjuvant treatment for obesity and related metabolic diseases.

MicroRNAs (miRNAs) secreted by cells into microvesicles (MVs) form a novel class of signal molecules that mediate intercellular communication. However, several fundamental aspects of secreted miRNAs remain unknown, particularly the mechanism that governs the function or fate of exogenous miRNAs in recipient cells. In the present study, we provide evidence indicating that Argonaute 2 (Ago2) plays a role in stabilizing miRNAs and facilitating the packaging of secreted miRNAs into MVs. More importantly, Ago2 in origin cell-secreted MVs (but not in recipient cells) directs the function of secreted miRNAs. First, Ago2 overexpression clearly increased the level of miR-16 in cells transfected with a miR-16 mimic by protecting the miRNAs from degradation in lysosomes. Second, Ago2 overexpression increased the level of miR-16 in cell-secreted MVs, suggesting that Ago2 may facilitate the packaging of secreted miRNAs into MVs. Third, exogenous miR-16 delivered by MVs within the origin cells significantly reduced the Bcl2 protein level in recipient cells, and miR-16 and Bcl2 mRNA were physically associated with exogenous HA-tagged Ago2 (HA-Ago2). Finally, the effect of MV-delivered miR-16 on the production of the Bcl2 protein in recipient cells was not abolished by knocking down Ago2 in the recipient cells.

SIRPα, an ITIMs-containing signaling receptor, negatively regulates leukocyte responses through extracellular interactions with CD47. However, the dynamics of SIRPα-CD47 interactions on the cell surface and the governing mechanisms remain unclear. Here we report that while the purified SIRPα binds to CD47 and that SIRPα is expressed on monocytes and monocytic THP-1 or U937, these SIRPα are ineffective to mediate cell binding to immobilized CD47. However, cell binding to CD47 is significantly enhanced when monocytes transmigrating across endothelia, or being differentiated into macrophages. Cell surface labeling reveals SIRPα to be diffused on naïve monocytes but highly clustered on transmigrated monocytes and macrophages. Protein crosslink and equilibrium centrifugation confirm that SIRPα in the latter cells forms oligomerized complexes resulting in increased avidity for CD47 binding. Furthermore, formation of SIRPα complexes/clusters requires the plasma membrane 'lipid rafts' and the activity of Src family kinase during macrophage differentiation. These results together suggest that 'clustering' SIRPα into plasma membrane microdomains is essential for activated monocytes and macrophages to effectively interact with CD47 and initiate intracellular signaling.

In uncertainty analysis and reliability-based multidisciplinary design and optimization (RBMDO) of engineering structures, the saddlepoint approximation (SA) method can be utilized to enhance the accuracy and efficiency of reliability evaluation. However, the random variables involved in SA should be easy to handle. Additionally, the corresponding saddlepoint equation should not be complicated. Both of them limit the application of SA for engineering problems. The moment method can construct an approximate cumulative distribution function of the performance function based on the first few statistical moments. However, the traditional moment matching method is not very accurate generally. In order to take advantage of the SA method and the moment matching method to enhance the efficiency of design and optimization, a fourth-moment saddlepoint approximation (FMSA) method is introduced into RBMDO. In FMSA, the approximate cumulative generating functions are constructed based on the first four moments of the limit state function. The probability density function and cumulative distribution function are estimated based on this approximate cumulative generating function. Furthermore, the FMSA method is introduced and combined into RBMDO within the framework of sequence optimization and reliability assessment, which is based on the performance measure approach strategy. Two engineering examples are introduced to verify the effectiveness of proposed method. [ABSTRACT FROM AUTHOR]

Actual engineering systems will be inevitably affected by uncertain factors. Thus, the Reliability-Based Multidisciplinary Design Optimization (RBMDO) has become a hotspot for recent research and application in complex engineering system design. The Second-Order/First-Order Mean-Value Saddlepoint Approximate (SOMVSA/FOMVSA) are two popular reliability analysis strategies that are widely used in RBMDO. However, the SOMVSA method can only be used efficiently when the distribution of input variables is Gaussian distribution, which significantly limits its application. In this study, the Gaussian Mixture Model-based Second-Order Mean-Value Saddlepoint Approximation (GMM-SOMVSA) is introduced to tackle above problem. It is integrated with the Collaborative Optimization (CO) method to solve RBMDO problems. Furthermore, the formula and procedure of RBMDO using GMM-SOMVSA-Based CO(GMM-SOMVSA-CO) are proposed. Finally, an engineering example is given to show the application of the GMM-SOMVSA-CO method. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) play a vital role in many biological processes, including cell growth, differentiation, apoptosis, development, differentiation, and carcinogenesis. Since miRNAs might play a part in cancer initiation and progression, they comprise an original class of promising diagnostic and prognostic molecular markers. In order to systematically understand the regulation of miRNA expression in cancers, the current study analyzed the miRNA expression profile in NCI-60 human cancer cell lines. Over 300 miRNAs exhibited unique expression profiles in cell lines derived from the same lineage. This study identified 9 lineage-specific miRNA expression patterns. Moreover, results indicated that miR-720 and miR-887 are expressed at relatively high levels in breast cancer cell lines compared to other types of cancer. Ultimately, matching NCI- 60 drug response data to miR-720 and miR-887 expression profiles revealed that several FDAapproved drugs were inversely related to miR-720 and miR-887. Furthermore, the anti-cancer effect of perifosine was significantly enhanced by inhibiting miR-720 and decreased by miR-720 precursor treatment in breast cancer cell lines. 5-Fu treatment was enhanced by inhibiting miR-887 and decreased by miR-887 precursor treatment. The current results offer insight into the relationship between miRNA expression and their lineage types, and the approach used here represents a potential cancer therapy with the help of miRNAs. [ABSTRACT FROM AUTHOR]

Rapid urbanization results in changes in land use, biogeochemical cycles, climate, hydrosystems, and biodiversity. Policy-makers have formulated ecological protection measures to facilitate sustainable development. However, traditional conservation planning mainly focuses on protecting specific green spaces, with limited consideration of the connectivity among green spaces from a habitat network perspective. Using citizen science data and occupancy modelling, we predicted habitat suitability, built habitat networks and identified key habitat patches based on their contribution to the functional connectivity of the habitat network for three focal water, forest, and open-habitat bird species. Based on the habitat requirement, small waterbodies and intermediate forest and open-habitat cover facilitate preserving water, forest and open-habitat birds. In regards to the network analysis, we found that key habitat patches with a high conservation priority were generally characterized by a relatively large patch size and/or located at critical positions in the habitat network (at central positions in the habitat network, or near large patches). We suggest that key habitat patches in restricted built-up areas are converted to protected areas or are kept as cropland under future urban planning. We emphasize the usefulness of the focal species concept in urban biodiversity conservation. Our study offers conservation recommendations from a habitat network perspective for urban planners to safeguard urban biodiversity and ecosystem health. [ABSTRACT FROM AUTHOR]

Rapid clearance of adoptively transferred Cd47-null (Cd47-/-) cells in congeneic WT mice suggests a critical self-recognition mechanism, in which CD47 is the ubiquitous marker of self, and its interaction with macrophage signal regulatory protein α (SIRPα) triggers inhibitory signaling through SIRPα cytoplasmic immunoreceptor tyrosinebased inhibition motifs and tyrosine phosphatase SHP-1/2. However, instead of displaying self-destruction phenotypes, Cd47-/- mice manifest no, or only mild, macrophage phagocytosis toward self-cells except under the nonobese diabetic background. Studying our recently established Sirpα-KO (Sirpα-/-) mice, as well as Cd47-/- mice, we reveal additional activation and inhibitory mechanisms besides the CD47-SIRPα axis dominantly controlling macrophage behavior. Sirpα-/- mice and Cd47-/- mice, although being normally healthy, develop severe anemia and splenomegaly under chronic colitis, peritonitis, cytokine treatments, and CFA-/LPS-induced inflammation, owing to splenic macrophages phagocytizing self-red blood cells. Ex vivo phagocytosis assays confirmed general inactivity of macrophages from Sirpα-/- or Cd47-/- mice toward healthy selfcells, whereas they aggressively attack toward bacteria, zymosan, apoptotic, and immune complex-bound cells; however, treating these macrophages with IL-17, LPS, IL-6, IL-1β, and TNFα, but not IFN?, dramatically initiates potent phagocytosis toward self-cells, for which only the Cd47-Sirpα interaction restrains. Even for macrophages from WT mice, phagocytosis toward Cd47-/- cells does not occur without phagocytic activation. Mechanistic studies suggest a PKC-Syk-mediated signaling pathway, towhich IL-10 conversely inhibits, is required for activating macrophage self-targeting, followed by phagocytosis independent of calreticulin. Moreover, we identified spleen red pulp to be one specific tissue that provides stimuli constantly activating macrophage phagocytosis albeit lacking in Cd47-/- or Sirpα-/- mice. [ABSTRACT FROM AUTHOR]

PGC-1α, a potent transcriptional coactivator, is the major regulator of mitochondrial biogenesis and activity in the cardiac muscle. The dysregulation of PGC-1α and its target genes has been reported to be associated with congenital and acquired heart diseases. By examining myocardium samples from patients with Tetralogy of Fallot, we show here that PGC-1α expression levels are markedly increased in patients compared with healthy controls and positively correlated with the severity of cyanosis. Furthermore, hypoxia significantly induced the expression of PGC-1α and mitochondrial biogenesis in cultured cardiac myocytes. Mechanistic studies suggest that hypoxia-induced PGC-1α expression is regulated through the AMPK signaling pathway. Together, our data indicate that hypoxia can stimulate the expression of PGC-1α and mitochondrial biogenesis in the cardiac myocytes, and this process might provide a potential adaptive mechanism for cardiac myocytes to increase ATP output and minimize hypoxic damage to the heart. [ABSTRACT FROM AUTHOR]